Delta-9- tetrahydrocannabinol (THC), the primary psychoactive cannabinoid, exerts the majority of its central nervous system effects through interaction with the G-protein linked cannabinoid CB1 receptor. A second cannabinoid-binding seven-transmembrane spanning receptor subtype, termed CB2, has been cloned and appears to be involved with regulation of immunological functions. SR 141716 or Rimonabant is the first antagonist of the central cannabinoid receptor CB1 to be identified. It antagonizes the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylcyclase activity in rat brain membranes. Availability of a pure cannabinoid receptor antagonist has helped to assess the role of the endogenous cannabinoid system. The potential therapeutic utility of this antagonist in modulating the large number of brain systems that appear to express cannabinoid CB1 receptors is especially interesting. Cannabinoid effects on "reward" systems could be mediated through moderate receptor densities in ventral tegmental area and the nucleus accumbens. We have shown for the first time the ability of Rimonabant to block the acute effects of THC in humans, thus confirming the parallelism of effects in humans and animals. We conducted a phase I clinical trial of the antagonism of the subjective and cardiovascular effects of smoked marijuana by Rimonabant. In addition, the safety of Rimonabant when given alone to light cannabis users, or in combination with THC via inhalation and the pharmacokinetics of Rimonabant and THC are being determined. Healthy male subjects with a history of cannabis use receive placebo or active Rimonabant prior to smoking placebo or active marijuana. Physiological, biochemical and behavioral measures are being monitored to evaluate pharmacodynamic effects. We are currently analyzing the results of the second phase I study of Rimonabant utilizing multiple doses to determine if a larger blockade of marijuana's effects can be accomplished with smaller multiple doses of drug.